Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis

In zebrafish mosaic mutagenesis, choline kinase alpha (CHKA) drives increased phosphatidylcholine biosynthesis in asxl1-mutant HSPCs, and CHKA-dependent choline flux suppression reduces ASXL1-driven clonal expansion.

• Why it matters: Clonal hematopoiesis has limited therapeutic options, yet it is linked to hematological malignancy, cardiovascular disease, and all-cause mortality.
• What they did: Using HSPC color barcoding and mosaic mutagenesis in zebrafish, the study tested CHKA-dependent choline flux and found it supports phosphatidylcholine production and platelet activating factor (PAF) production; CHKA inhibition was evaluated in murine DNMT3A and human TET2 models, with exogenous PAF used for rescue.
• The result: CHKA inhibition suppressed clonal expansion across ASXL1, DNMT3A, and TET2 models, while exogenous PAF overcame this suppression in ASXL1 and TET2; in primary human ASXL1-mutant HSPCs, perturbing PAF signaling reduced competitive potential ex vivo, and the CHKA/PAF axis was conserved in TET2-mutant HSPCs.